The present invention relates to a novel process for the purification of poloxamers which contain aldehyde impurities, and particularly for the purification of the poloxamers named poloxamer 188 and poloxamer 407.
Poloxamers are synthetic block copolymers of hydrophilic ethylene oxide chains and hydrophobic propylene oxide chains, having the formula HOxe2x80x94[C2H4O]axe2x80x94[C3H6O]bxe2x80x94[C2H4O]axe2x80x94H, wherein a and b represent the number of hydrophilic and hydrophobic chains respectively.
The poloxamers can be used as surfactants, emulsifying agents, solubilizing agents or wetting agents in different compositions. WO97/38675 discloses a composition comprising one or more local anaesthetics, water and one or more surfactants, preferably poloxamer(s). Since the poloxamers have both hydrophobic and hydrophilic domains they can, in combination with for example a local anaesthetic, provide a composition having thermoreversible gelling properties.
Commercially available poloxamers often contain relatively high amounts of aldehydes. These aldehydes may react with the active compound, for example a local anaesthetic, and form non-desirable compounds which have to be separated from the final product. This also means that a higher amount of the active compound is required, since some of the active compound is reacting with the aldehydes and thus is lost during the purification process.
Thus, there is a need for an improved purification process in order to reduce the concentration of aldehydes in poloxamers.
The present invention is directed to a novel process for the purification of poloxamers, which contain aldehyde impurities, whereby
(i) the poloxamer(s) is dissolved in a solvent, which solvent may optionally contain an acid or a mixture of acids,
(ii) if the solvent in which the poloxamer(s) has been dissolved is free from acid, acid is added; whereafter
(iii) the aldehydes are removed.
The process according to the present invention is suitable for the purification of poloxamers containing aldehyde impurities, said poloxamers having the general formula HOxe2x80x94[C2H4O]axe2x80x94[C3H6O]bxe2x80x94[C2H4O]axe2x80x94H, wherein a and b represent the number of hydrophilic and hydrophobic chains. The process according to the present invention is particularly suitable for the purification of Lutrol F68(copyright), which also has the name poloxamer 188 and wherein a=80 and b=27, or Lutrol F127(copyright),which also has the name poloxamer 407 and wherein a=101 and b=56, the definitions being in accordance with USP (1995) HF18, p.2279. The process may also be used for the purification of a mixture of poloxamers, and specifically a mixture of poloxamer 188 and poloxamer 407, as well as for the purification of other polymers containing monomers such as ethylene oxide, propylene oxide or similar, said polymers containing aldehyde impurities.
The solvent used for dissolving the poloxamer may be water, an alcohol such as methanol. ethanol or propanol, or any other suitable solvent. Preferably water is used as a solvent.
The temperature of the solvent or the mixture of solvent and poloxamer is not essential, however, the poloxamer is dissolved more quickly at a temperature below room temperature. A preferred solvent temperature is from 0 to +10xc2x0 C.
The concentration of poloxamer in the poloxamer solution is preferably 5-21% by weight.
More preferred the concentration is 15% by weight.
The acid(s) added to the poloxamer solution may be any acid(s), but preferably one or a mixture of two or more of hydrochloric acid, acetic acid or citric acid. More preferably the acid is one or a mixture of hydrochloric acid or acetic acid, but most preferred is to use acetic acid alone. pH for the solution after having added the acid should be from 1-7, preferably from 1-5. The amount of added acid is dependent on the desired pH.
The acid or acids may be added to the solvent before or after the poloxamer is added to the solvent. When the poloxamer and the acid have been added to the solvent, and the poloxamer is dissolved, the acid needs some time to interact, whereafter the aldehydes are removed from the solution by drying. The drying may be evaporation performed by boiling the solution, whereby the aldehydes are vaporized, drying the solution on a fluid bed, spray drying, freeze drying, vacuum evaporation or letting a stream of gas, such as helium or nitrogen, pass through the solution, spray crystallisation, spray granulation or any other method of drying known to the skilled person. Preferably the aldehydes are evaporated by drying the solution on a fluid bed and at a temperature as of  less than 47xc2x0 C. for the poloxamer. A higher temperature provides a quicker drying of the solution, but the temperature may however not be too high since the poloxamers may melt at higher temperatures.
The process according to present invention is particularly suitable for the removal of formaldehyde, acetaldehyde and propionaldehyde from poloxamers. Other aldehyde impurities may however also be removed by using the process according to the present invention. The present process is particularly suitable for the removal of acetaldehyde and propionaldehyde from poloxamers.
Also within the scope of the invention is a poloxamer purified from aldehydes according to the process described above.
The reduction of aldehydes in the following Examples has been determined according to the analytical method described below.
Analytical Method
The sample is dissolved and diluted in water. Any aldehydes present in the poloxamers will react with 2,4-dinitrophenylhydrazine or 3-methyl-2-benzothiazolonehydrazone at room temperature to form derivatives. The derivatives are extracted with cyclohexane followed by evaporation of the organic phase. The residual is dissolved in the mobile phase and the derivates are separated using liquid chromatography and quantified by standard addition or external standard calibration.